Epigenetic Regulation of MAP3K8 in EBV-Associated Gastric Carcinoma

• Published in: International journal of molecular sciences Vol. 24; no. 3; p. 1964
• Main Authors: Roy, Gaurab, Yang, Ting, Liu, Shangxin, Luo, Yi-Ling, Liu, Yuantao, Zhong, Qian
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19-01-2023; MDPI
• Subjects: Actin; Breast cancer; Cell cycle; Cell proliferation; Chromosomes; Colorectal cancer; Correlation; CRISPR interference (CRISPRi); DNA methylation; Enhancers; Epigenesis, Genetic - genetics; Epigenetics; Epstein-Barr virus; Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - pathology; Epstein–Barr virus-associated gastric carcinoma (EBVaGC); Functional analysis; Gastric cancer; Gene Expression Regulation, Neoplastic - genetics; Genes; Genomes; Growth factors; Herpesvirus 4, Human - genetics; Humans; Infections; Kinases; Liver cancer; MAP kinase; MAP Kinase Kinase Kinases - genetics; Melanoma; Mesenchyme; Metastasis; mitogen-activated protein kinase 8 (MAP3K8); Muscles; Proteins; Proto-Oncogene Proteins - genetics; Repressors; Signal transduction; Smooth muscle; Snail protein; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Stomach Neoplasms - virology; super-enhancer (SE); Transcription factors; Tumorigenesis; super-enhancer (SE); mitogen-activated protein kinase 8 (MAP3K8); Epstein–Barr virus-associated gastric carcinoma (EBVaGC); CRISPR interference (CRISPRi); epigenetics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24031964

Super-enhancers (SEs) regulate gene expressions, which are critical for cell type-identity and tumorigenesis. Although genome wide H3K27ac profiling have revealed the presence of SE-associated genes in gastric cancer (GC), their roles remain unclear. In this study, ChIP-seq and HiChIP-seq experiments revealed mitogen-activated protein kinase 8 (
) to be an SE-associated gene with chromosome interactions in Epstein-Barr virus-associated gastric carcinoma (EBVaGC) cells. CRISPRi mediated repression of the
SEs attenuated
expression and EBVaGC cell proliferation. The results were validated by treating EBVaGC cells with bromodomain and the extra-terminal motif (BET) inhibitor, OTX015. Further, functional analysis of
in EBVaGC revealed that silencing
could inhibit the cell proliferation, colony formation, and migration of EBVaGC cells. RNA-seq and pathway analysis indicated that knocking down
obstructed the notch signaling pathway and epithelial-mesenchymal transition (EMT) in EBVaGC cells. Further, analysis of the cancer genome atlas (TCGA) and GSE51575 databases exhibited augmented
expression in gastric cancer and it was found to be inversely correlated with the disease-free progression of GC. Moreover, Spearman's correlation revealed that
expression was positively correlated with the expressions of notch pathway and EMT related genes, such as,
C-terminal binding protein 2 (
), alpha smooth muscle actin isotype 2 (
), transforming growth factor beta receptor 1 (
), and snail family transcriptional repressors 1/2 (
/
) in GC. Taken together, we are the first to functionally interrogate the mechanism of SE-mediated regulation of
in EBVaGC cell lines.